Much of the prior work with rodent lines selectively bred for differences in alcohol intake has focused on the reinforcing effects of alcohol that promote and maintain high alcohol drinking behavior. This proposal focuses on the aversive effects of alcohol that may also influence alcohol drinking behavior in both alcohol-naive and alcohol-experienced animals. We will determine whether innate differences in sensitivity to alcohol withdrawal (AW) are associated with genetic differences in alcohol drinking behavior in rat lines selectively bred for alcohol preference and -nonpreference (P/NP and replicate HAD/LAD lines). While these lines have been well characterized on several alcohol-related traits that are thought to contribute to the reinforcing properties of alcohol, the lines have not been characterized in terms of sensitivity to the aversive properties of alcohol. Preliminary data are presented which suggest that rats selectively bred for alcohol nonpreference (NP line) evidence greater AW severity after acute or chronic exposure to a given dose of alcohol than do their counterparts selectively bred for alcohol preference (P line). In Specific Aim (SA) 1 we will characterize and compare sensitivity to AW, as well as alcohol aversion threshold, in rats of the P/NP and replicate HAD/LAD lines following acute and chronic alcohol treatment. In SA 2 we will determine whether sensitization or tolerance develops to AW in each of the selected lines following chronic alcohol exposure using a procedure that maintains steady state blood alcohol levels (the "alcohol clamp"). In SA 3 we will explore the relationship between AW severity and probability of subsequent alcohol drinking in each selected line. In SA 4 we will investigate the interaction between the opioid and hypothalamic-pituitary- adrenal (HPA) systems in mediating AW severity. We hypothesize that increased sensitivity to AW may be a trait that, when inherited, serves to protect against high alcohol drinking in rodent lines selectively bred for low alcohol preference. Recognizing the importance of demonstrating that the relationship between the phenotype (alcohol drinking) and the related-trait (sensitivity to AW) exists in more than one line selected for the same phenotype, the majority of the proposed studies will be conducted in three sets of rat lines selectively bred for differences in alcohol preference (P/NP and replicate HAD/LAD lines).